A Novel CCR5 Mutation Common in Sooty Mangabeys Reveals SIVsmm Infection of CCR5-Null Natural Hosts and Efficient Alternative Coreceptor Use In Vivo

PLoS Pathogens

Jessica C. Engram¹  Lamorris M. Loftin¹  Barbara Cervasi¹  Nadeene E. Riddick¹  Sarah T. Elliott¹  Jessica Taaffe²  Winston C. Wey²  Emilia A. Hermann²  James G. Else²  Ronald G. Collman³  Beatrice H. Hahn⁴  Yingying Li⁴  Bing Li⁴  Mirko Paiardini⁵  Cristian Apetrei⁵  Cynthia A. Derdeyn⁶  Donald L. Sodora⁶  Guido Silvestri⁶ 

[1] Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America;Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America;Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America;Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America;Departments of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America;Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America

关键词: Coreceptors;    Variant genotypes;    SIV;    T cells;    CCR5 coreceptor;    Alleles;    Macaque;    Polymerase chain reaction;   

DOI  :  10.1371/journal.ppat.1001064

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

In contrast to HIV infection in humans and SIV in macaques, SIV infection of natural hosts including sooty mangabeys (SM) is non-pathogenic despite robust virus replication. We identified a novel SM CCR5 allele containing a two base pair deletion (Δ2) encoding a truncated molecule that is not expressed on the cell surface and does not support SIV entry in vitro. The allele was present at a 26% frequency in a large SM colony, along with 3% for a CCR5Δ24 deletion allele that also abrogates surface expression. Overall, 8% of animals were homozygous for defective CCR5 alleles and 41% were heterozygous. The mutant allele was also present in wild SM in West Africa. CD8+ and CD4+ T cells displayed a gradient of CCR5 expression across genotype groups, which was highly significant for CD8+ cells. Remarkably, the prevalence of natural SIVsmm infection was not significantly different in animals lacking functional CCR5 compared to heterozygous and homozygous wild-type animals. Furthermore, animals lacking functional CCR5 had robust plasma viral loads, which were only modestly lower than wild-type animals. SIVsmm primary isolates infected both homozygous mutant and wild-type PBMC in a CCR5-independent manner in vitro, and Envs from both CCR5-null and wild-type infected animals used CXCR6, GPR15 and GPR1 in addition to CCR5 in transfected cells. These data clearly indicate that SIVsmm relies on CCR5-independent entry pathways in SM that are homozygous for defective CCR5 alleles and, while the extent of alternative coreceptor use in SM with CCR5 wild type alleles is uncertain, strongly suggest that SIVsmm tropism and host cell targeting in vivo is defined by the distribution and use of alternative entry pathways in addition to CCR5. SIVsmm entry through alternative pathways in vivo raises the possibility of novel CCR5-negative target cells that may be more expendable than CCR5+ cells and enable the virus to replicate efficiently without causing disease in the face of extremely restricted CCR5 expression seen in SM and several other natural host species.

【 授权许可】

CC BY